title: Cyclosporin A induces cardiomyocyte injury through calcium-sensing receptor-mediated calcium overload.
abstract: The aim of this study was to investigate whether Cyclosporin-A (CsA)-induced myocardial injury is mediated by elevating the intracellular calcium concentration ([Ca2+]i) through the Calcium sensing receptor (CaSR). Cultured neonatal rat cardiomyocytes were treated with CsA, with or without pretreatment with the CaSR-specific antagonist NPS2390 or the CaSR-specific agonist gadolinium chloride (GdCI3). At 2 h, 4 h, 6 h and 8 h after CsA treatment, the ultrastructural changes of the cardiomyocytes were observed. In addition, the lactate dehydrogenase (LDH) and creatine kinase (CK) release from the cardiomyocytes, the [Ca2+]i and the level of CaSR expression were determined. With increasing time of CsA treatment, ultrastructural damage of cardimyocytes gradually aggrevated, LDH and CK release and [Ca2+]i also gradually increased. CaSR mRNA and protein expression increased at 4 h after CsA treatment. Compared with CsA treatment alone, pretreatment with NPS2390 lessened the ultrastructural damage of the cardiomyocytes as well as decreased the LDH and CK release, [Ca2+]i and the expression of the CaSR mRNA and protein. Conversely, pretreatment with GdCI3 aggravated the ultrastructural damage of the cardiomyocytes as well as increased LDH and CK release, [Ca2+]i and the expression of the CaSR mRNA and protein. These results demonstrate that CsA induced cardiomyocyte injury in a time-dependent manner. Moreover, CsA-induced cardiomyocyte injury was related to CaSR-mediated intracellular calcium overload. These findings provide new insight into the mechanisms involved in CsA-induced myocardial injury.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jiebing
authors.initials: J
authors.lastname: Tang
authors.forename: Guixiang
authors.initials: G
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Jinyu
authors.initials: J
authors.lastname: Chi
authors.forename: Yejing
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yanru
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000633:toxicity*; D003402:Creatine Kinase / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D005682:Gadolinium / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D016572:Cyclosporine; D005682:Gadolinium; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; C038958:gadolinium chloride; D002118:Calcium